Hsp60 and Hsp10 as antitumour molecular agents

The molecular chaperones Hsp60 and Hsp10 are, according to recent reports, involved in cancer development and progression. We, for instance, have found that their expression varies with distinctive patterns in different malignancies: they are overexpressed in colorectal, exocervical and prostate carcinogenesis, and colorectal cancer progression, but they are downregulated during bronchial carcinogenesis. There is also evidence showing that Hsp60 and Hsp10 can be used as therapeutic agents, for example in rheumatoid arthritis. In view of these findings we want now to call attention to the potential of Hsp60 and Hsp10 in cancer therapy.

TLR4 and NOD1 increase in stable COPD of increasing severity. Relationship with tissutal bacterial load

Background: The immune host response related to bacterial and viral infections in the airways and lung of COPD patients is unclear. Objectives: To investigate the expression of anti-bacterial and anti-viral antigens in bronchial biopsies and lung parenchyma of stable COPD patients in relation to bacterial load. Methods: Immunohistochemical (IHC) and qRT-PCR-expression of TLR2-3-4-7-8-9, NOD1, NOD2, MYD88, TRIF, TIRAP, pIRAK1, IRAK4, IRF3, pIRF3, IRF7, pIRF7, RIG1, MDA5, LGP2, MAVS, STING, DAI, IFNα and IFNβ was measured in bronchial mucosa in patients with mild/moderate (n=16), severe/very severe (n=18) stable COPD, control smokers (n=12) and control non-smokers (n=12). Selected relevant an…

High-resolution computed tomography quantitation of emphysema is correlated with selected lung function values in stable COPD

<b><i>Background:</i></b> The literature shows conflicting results when high-resolution computed tomography (HRCT) scores of emphysema were correlated with different indices of airflow obstruction. <b><i>Objectives:</i></b> We correlated HRCT scores of emphysema with different indices of airflow obstruction. <b><i>Methods:</i></b> We performed HRCT of the chest in 59 patients, all smokers or ex-smokers, with stable chronic obstructive pulmonary disease of different severity [GOLD stages I–IV; mean age ± SD 67.8 ± 7.3 years; pack/years 51.0 ± 34.6; percent predicted forced expiratory volume in 1 s (FEV<sub>1</su…

Hsp60 and Hsp10 down-regulation predicts bronchial epithelial carcinogenesis in smokers with chronic obstructive pulmonary disease.

BACKGROUND. The relation between smoking, chronic obstructive pulmonary disease (COPD), and lung cancer (LC) is an open field of investigation. A higher frequency of adenocarcinoma has been reported in patients with COPD. Heat shock proteins (Hsps) are implicated in tumoral cell growth and differentiation. The aim of the present study was to investigate the expression of Hsp60 and Hsp10 in bronchial biopsies from smokers with COPD and in 10 lung cancer patients and to evaluate the association between Hsps expression and carcinogenetic steps of LC. METHODS. An immunohistochemical study was performed for Hsp60 and Hsp10 in bronchial biopsies from 35 COPD (postbronchodilator forced expiratory …

Hsp27 and Hsp70 in chronic obstructive pulmonary disease: certainties vs doubts

Dear Editor, We read with great interest the work by Cui et al. (2015) in which they measured the levels of Hsp70 and Hsp27 in plasma and lymphocytes obtained from coal workers (CW) affected by chronic obstructive pulmonary disease (COPD) alone or associated with pneumoconiosis (CWP). They found that Hsp70 levels were higher in plasma of COPD subjects affected by CWP compared to COPD subjects without CWP and to controls. There was no difference in Hsp70 levels between COPD without CWP and controls. Hsp70 levels in lymphocytes did not show differences among the three groups. The authors found lower levels of Hsp27 in plasma from patients when comparing controls to both COPD with and without …

Bacterial and viral infections and related inflammatory responses in chronic obstructive pulmonary disease

Abstract In chronic obstructive pulmonary disease (COPD) patients, bacterial and viral infections play a relevant role in worsening lung function and, therefore, favour disease progression. The inflammatory response to lung infections may become a specific indication of the bacterial and viral infections. We here review data on the bacterial–viral infections and related airways and lung parenchyma inflammation in stable and exacerbated COPD, focussing our attention on the prevalent molecular pathways in these different clinical conditions. The roles of macrophages, autophagy and NETosis are also briefly discussed in the context of lung infections in COPD. Controlling their combined response…

Role of oxidative and nitrosative stress biomarkers in chronic heart failure

In this review, we present recent insights on chronic heart failure (CHF) and the potential role of tumor necrosis factor (TNF)-alpha, interleukins, myeloperoxidase (MPO), and nitrosative stress in the progression of this disease process. Reactive oxygen species (ROS) are produced as a consequence of aerobic metabolism. Under physiologic conditions, their unfavourable effect in causing oxidative damage is counteracted by antioxidants. An imbalance in favour of oxidants leads to oxidative stress, and contributes to myocyte apoptosis, direct negative inotropic effects, and reduced bioavailability of nitric oxide (NO). Together, these effects lead to impaired vasodilatation of the coronary, pu…

Aerobic training and angiogenesis activation in patients with stable chronic heart failure: a preliminary report.

The pathophysiology of chronic heart failure (CHF) involves multiple hystologic and molecular alterations. To determine the effects of physical training on circulating endothelial progenitor cells (EPCs), angiogenesis (angiogenin, angiopoietin-1 and -2, VEGF, Tie-2, SDF-1α) and inflammation (IL-6, CRP), we compared data obtained from 11 CHF pts before and after 3 months aerobic exercise training, to those from 10 non trained CHF pts (CHF-C group, age 64 + 2 years, NYHA 2). At the end of the study, EPCs count and AP-2 serum levels significantly increased in the CHF-TR group. These preliminary data suggest a significant effect of even a short program of physical training on angiogenic activat…

Increased nitrotyrosine plasma levels in relation to systemic markers of inflammation and myeloperoxidase in chronic heart failure

The presence of a reciprocal link between inflammation and oxidative/nitrosative stress has been postulated in chronic heart failure (CHF). We aimed to determine signs of nitrosative stress in serum/plasma of CHF patients. ELISA tests were used for quantification of serum/plasma levels of Nitrotyrosine (NT), H(2)O(2), total NO, nitrite (NO(2)(-)), myeloperoxidase (MPO), Tumor Necrosis Factor-alpha (TNFalpha) and pro-Brain Natriuretic Peptide (proBNP) in 66 CHF patients (9 in NYHA I, 34 NYHA II, 23 NYHA III) and in 14 age-matched healthy subjects. NT levels were higher in NYHA III CHF patients compared to NYHA II (p<0.05), NYHA I (p<0.03) and controls (p<0.02), whereas NO(2)(-) and total NO …

&lt;p&gt;Bacterial load and inflammatory response in sputum of alpha-1 antitrypsin deficiency patients with COPD&lt;/p&gt;

Background Airway inflammation may drive the progression of chronic obstructive pulmonary disease (COPD) associated with alpha-1 antitrypsin deficiency (AATD), but the relationship between airway microbiota and inflammation has not been investigated. Methods We studied 21 non-treated AATD (AATD-noT) patients, 20 AATD-COPD patients under augmentation therapy (AATD-AT), 20 cigarette smoke-associated COPD patients, 20 control healthy smokers (CS) and 21 non-smokers (CON) with normal lung function. We quantified sputum inflammatory cells and inflammatory markers (IL-27, CCL3, CCL5, CXCL8, LTB4, MPO) by ELISA, total bacterial load (16S) and pathogenic bacteria by qRT-PCR. Results AATD-AT patient…

Phospho-p38 MAPK expression in COPD patients and asthmatics and in challenged bronchial epithelium

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; The role of mitogen-activated protein kinases (MAPK) in regulating the inflammatory response in the airways of patients with chronic obstructive pulmonary disease (COPD) and asthmatic patients is unclear. &lt;b&gt;&lt;i&gt;Objectives:&lt;/i&gt;&lt;/b&gt; To investigate the expression of activated MAPK in lungs of COPD patients and in bronchial biopsies of asthmatic patients and to study MAPK expression in bronchial epithelial cells in response to oxidative and inflammatory stimuli. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; Immunohistochemical expression of phospho (p)-p38 MAPK, p-JNK1 and p-ERK1/2 was measured in bronchial mucosa in pat…

Immunopositivity of heat shock protein 60 as a biomarker of bronchial carcinogenesis

Bronchial inflammation and bacterial load in stable COPD is associated with TLR4 overexpression.

Toll-like receptors (TLRs) and nucleotide-binding oligomerisation domain (NOD)-like receptors (NLRs) are two major forms of innate immune sensors but their role in the immunopathology of stable chronic obstructive pulmonary disease (COPD) is incompletely studied. Our objective here was to investigate TLR and NLR signalling pathways in the bronchial mucosa in stable COPD.Using immunohistochemistry, the expression levels of TLR2, TLR4, TLR9, NOD1, NOD2, CD14, myeloid differentiation primary response gene 88 (MyD88), Toll-interleukin-1 receptor domain-containing adaptor protein (TIRAP), and the interleukin-1 receptor-associated kinases phospho-IRAK1 and IRAK4 were measured in the bronchial muc…

Oxidative stress induces myeloperoxidase expression in endocardial endothelial cells from patients with chronic heart failure.

Increased oxidative stress has been implicated in the pathogenesis of a number of cardiovascular diseases. Recent findings suggest that myeloperoxidase (MPO) may play a key role in the initiation and maintenance of chronic heart failure (CHF) by contributing to the depletion of the intracellular reservoir of nitric oxide (NO). NO consumption through MPO activity may lead to protein chlorination or nitration, leading to tissue damage. Primary cultures of human endocardial endothelial cells (EEC) obtained at heart transplantation of patients with CHF and human umbilical vein endothelial cells (HUVEC) were subjected to oxidative stress by incubation with hydrogen peroxide at non lethal (60 mic…

Isolation and characterization of Oct-4+/HLA-G+ mesenchymal stem cells from human umbilical cord matrix: differentiation potential and detection of new markers

The presence of multipotent cells in several adult and embryo-related tissues opened new paths for their use in regenerative medicine. Extraembryonic tissues such as umbilical cord are considered a promising source of stem cells, potentially useful in therapy. The characterization of cells from the umbilical cord matrix (Wharton''s Jelly) and amniotic membrane revealed the presence of a population of mesenchymal-like cells, sharing a set of core-markers expressed by "mesenchymal stem cells". Several reports enlightened the differentiation capabilities of these cells, even if at times the lack of an extensive characterization of surface markers and immune co-stimulators expression revealed h…

Pro-and anti-fibrotic molecule balance in the bronchial mucosa of stable COPD patients

Background: The mechanisms of inducing fibrotic events and remodeling in the airways of COPD are incompletely studied. Objectives: To investigate the expression of cytokines involved in the pro- and anti-fibrotic events in stable COPD. Methods: Expression of CTGF, TGFβ1-2-3, TGFβRI, TGFβRII, LTBP-1, TRAP-1, BAMBI, PP2Cα, Smad2-3-6-7, pSmad2, pSmad3, pro-collagen-I and collagen-I was measured in the bronchial mucosa using immunohistochemistry and RT-qPCR. Results: TGFβ1 was increased in the epithelium and TGFβ3 in the submucosa of healthy smokers and mild/moderate COPD compared to healthy non-smokers. In all smokers and patients with COPD TGFβ3+ cells in the submucosa correlated significantl…

HSP60 activity on human bronchial epithelial cells

HSP60 has been implicated in chronic inflammatory disease pathogenesis, including chronic obstructive pulmonary disease (COPD), but the mechanisms by which this chaperonin would act are poorly understood. A number of studies suggest a role for extracellular HSP60, since it can be secreted from cells and bind Toll-like receptors; however, the effects of this stimulation have never been extensively studied. We investigated the effects (pro- or anti-inflammatory) of HSP60 in human bronchial epithelial cells (16-HBE) alone and in comparison with oxidative, inflammatory, or bacterial challenges. 16-HBE cells were cultured for 1–4 h in the absence or presence of HSP60, H2O2, lipopolysaccharide (…

Downregulation of IL-27 bronchial epithelial expression by heat-shock protein-60

Background Heat-shock protein 60 (Hsp60) is ubiquitous and highly conserved Molecular chaperone. Hsp60 plays an important role in protein folding, inflammation, and tissue repair. We previously reported increased levels of HSP60 in COPD patients, suggesting a role for HSP60 in the inflammatory response in COPD. This study is aimed to evaluate the HSP60 immunomodulatory activity and Th1/Tc1 cytokines (IL-27/INFγ) production in Human Bronchial Epithelial cells line (16HBE). Methods 16HBE were plated in 6 wells plate with Dulbecco’s modified Minimum Essential Medium (DMEM) and exposed to various concentrations of HSP60 protein (1 ng/mL, 100 ng/mL and 1 µg/mL) for 8 and 24 hours. Induction of H…

Perinatal and Wharton's jelly-derived mesenchymal stem cells in cartilage regenerative medicine and tissue engineering strategies

Stem cells can be found in embryonic and extraembryonic tissues as well as in adult organs. In particular, research in the last few years has delineated the key features of perinatal stem cells derived from fetus-associated tissues. These cells show multiple differentiation potential, can be easily expanded ex vivo, and raise no ethical concerns as regards their use. Several reports indicate that cells isolated from Wharton's jelly (WJ), the main component of umbilical cord extracellular matrix, are multipotent stem cells that express markers shared by other mesenchymal stem cells (MSC) and give rise to different mature cell types belonging to all three germ layers. Moreover, WJ-MSC display…

Hsp60 and Hsp10 in Ageing

HSP and molecular chaperones, both referred to in this chapter as chaperones, are key players in development and senescence. With regard to senescence, several issues are critical: the role of normal chaperones in the process of ageing itself and in preventing and controlling age-associated diseases, the role of defective chaperones (chaperonopathies) in the onset and progression of senescence and in the etiology of old-age diseases, the interaction of chaperones with the immune system, and the potential of chaperones as therapeutic agents for counteracting the deleterious effects of ageing on molecules and cells and for treating proteinopathies of the elderly (chaperonotherapy). All these …

Fibrosis markers and CRIM1 increase in chronic heart failure of increasing severity.

AbstractBackground: Fibrosis suppressors/activators in chronic heart failure (CHF) is a topic of investigation.Aim: To quantify serum levels of fibrosis regulators in CHF.Methods: ELISA tests were used to quantify fibrosis regulators, procollagen type-(PIP)I, (PIP)III, collagen-I, III, BMP1,2,3,7, SDF1α, CXCR4, fibulin 1,2,3, BMPER, CRIM1 and BAMBI in 66 CHF (NYHA class I, n = 9; II, n = 34; III n = 23), and in 14 controls.Results: In CHF, TGFβR2, PIPIII, SDF1α and CRIM1 were increased. PIPIII correlated with CRIM1.Conclusions: The BMPs inhibitor CRIM1 is increased and correlates with higher levels of serum PIPIII showing an imbalance in favor of pro-fibrotic mechanisms in CHF.

Extracorporeal shock waves increase markers of cellular proliferation in primary bronchial fibroblasts of COPD patients

COPD is due to a remodeling of small airways and destruction of the lung parenchyma with loss of the alveolar attachment as a result of pulmonary emphysema. Treatment of connective tissue fibroblasts with extracorporeal shock waves (ESW) increases their cellular proliferation and differentiation. To date no studies are available on ESW treatment of human primary bronchial fibroblasts from COPD and control subjects. Primary bronchial fibroblasts were obtained from bronchial biopsies from three patients with mild/moderate COPD and 3 control smokers with normal lung function. After stabilization for 24h, 1 ml of cell suspension (106 cells) from COPD and controls was treated in 2 ml tubes with …

Extracorporeal Shock Waves Increase Markers of Cellular Proliferation in Bronchial Epithelium and in Primary Bronchial Fibroblasts of COPD Patients

Chronic obstructive pulmonary disease (COPD) is due to structural changes and narrowing of small airways and parenchymal destruction (loss of the alveolar attachment as a result of pulmonary emphysema), which all lead to airflow limitation. Extracorporeal shock waves (ESW) increase cell proliferation and differentiation of connective tissue fibroblasts. To date no studies are available on ESW treatment of human bronchial fibroblasts and epithelial cells from COPD and control subjects. We obtained primary bronchial fibroblasts from bronchial biopsies of 3 patients with mild/moderate COPD and 3 control smokers with normal lung function. 16HBE cells were also studied. Cells were treated with a…

Hsp10 nuclear localization and changes in lung cells response to cigarette smoke suggest novel roles for this chaperonin

Heat-shock protein (Hsp)10 is the co-chaperone for Hsp60 inside mitochondria, but it also resides outside the organelle. Variations in its levels and intracellular distribution have been documented in pathological conditions, e.g. cancer and chronic obstructive pulmonary disease (COPD). Here, we show that Hsp10 in COPD undergoes changes at the molecular and subcellular levels in bronchial cells from human specimens and derived cell lines, intact or subjected to stress induced by cigarette smoke extract (CSE). Noteworthy findings are: (i) Hsp10 occurred in nuclei of epithelial and lamina propria cells of bronchial mucosa from non-smokers and smokers; (ii) human bronchial epithelial (16HBE) a…

Bacterial-viral load and the immune response in stable and exacerbated COPD: significance and therapeutic prospects.

Silvestro Ennio D&rsquo;Anna,1 Bruno Balbi,2 Francesco Cappello,3,4 Mauro Carone,2 Antonino Di Stefano21Department of Rehabilitation, Cardiorespiratory Unit, Fondazione Istituto G. Giglio di Cefal&ugrave;, 2Pneumology Unit and Laboratory of Cytoimmunopathology of Heart and Lung, Fondazione Salvatore Maugeri, IRCCS, Veruno (NO) and Cassano delle Murge (BA), 3Human Anatomy Section, Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy; 4Euro-Mediterranean Institute of Science and Technology, Palermo, ItalyAbstract: Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and an abnormal inflammatory respon…

Bacterial&amp;ndash;viral load and the immune response in stable and exacerbated COPD: significance and therapeutic prospects

Silvestro Ennio D&amp;rsquo;Anna,1 Bruno Balbi,2 Francesco Cappello,3,4 Mauro Carone,2 Antonino Di Stefano21Department of Rehabilitation, Cardiorespiratory Unit, Fondazione Istituto G. Giglio di Cefal&amp;ugrave;, 2Pneumology Unit and Laboratory of Cytoimmunopathology of Heart and Lung, Fondazione Salvatore Maugeri, IRCCS, Veruno (NO) and Cassano delle Murge (BA), 3Human Anatomy Section, Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy; 4Euro-Mediterranean Institute of Science and Technology, Palermo, ItalyAbstract: Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and an abnormal inflammator…

TGF-β Signaling Pathways in Different Compartments of the Lower Airways of Patients With Stable COPD

Background: The expression and localization of transforming growth factor-β (TGF-β) pathway proteins in different compartments of the lower airways of patients with stable COPD is unclear. We aimed to determine TGF-β pathway protein expression in patients with stable COPD. Methods: The expression and localization of TGF-β pathway components was measured in the bronchial mucosa and peripheral lungs of patients with stable COPD (n = 44), control smokers with normal lung function (n = 24), and control nonsmoking subjects (n = 11) using immunohistochemical analysis. Results: TGF-β1, TGF-β3, and connective tissue growth factor expression were significantly decreased in the bronchiolar epithelium…

Isolation and Characterization of CD276+/HLA-E+ Human Subendocardial Mesenchymal Stem Cells from Chronic Heart Failure Patients: Analysis of Differentiative Potential and Immunomodulatory Markers Expression

Mesenchymal stem cells (MSCs) are virtually present in all postnatal organs as well as in perinatal tissues. MSCs can be differentiated toward several mature cytotypes and interestingly hold potentially relevant immunomodulatory features. Myocardial infarction results in severe tissue damage, cardiomyocyte loss, and eventually heart failure. Cellular cardiomyoplasty represents a promising approach for myocardial repair. Clinical trials using MSCs are underway for a number of heart diseases, even if their outcomes are hampered by low long-term improvements and the possible presence of complications related to cellular therapy administration. Therefore, elucidating the presence and role of MS…

Convergent sets of data from in vivo and in vitro methods point to an active role of Hsp60 in chronic obstructive pulmonary disease pathogenesis.

BackgroundIt is increasingly clear that some heat shock proteins (Hsps) play a role in inflammation. Here, we report results showing participation of Hsp60 in the pathogenesis of chronic obstructive pulmonary diseases (COPD), as indicated by data from both in vivo and in vitro analyses.Methods and resultsBronchial biopsies from patients with stable COPD, smoker controls with normal lung function, and non-smoker controls were studied. We quantified by immunohistochemistry levels of Hsp10, Hsp27, Hsp40, Hsp60, Hsp70, Hsp90, and HSF-1, along with levels of inflammatory markers. Hsp10, Hsp40, and Hsp60 were increased during progression of disease. We found also a positive correlation between th…

Wharton’s Jelly Mesenchymal Stem Cells as Candidates for Beta Cells Regeneration: Extending the Differentiative and Immunomodulatory Benefits of Adult Mesenchymal Stem Cells for the Treatment of Type 1 Diabetes

Mesenchymal stem cells (MSC) are uniquely capable of crossing germinative layers borders (i.e. are able to differentiate towards ectoderm-, mesoderm- and endoderm-derived cytotypes) and are viewed as promising cells for regenerative medicine approaches in several diseases. Type I diabetes therapy should potentially benefit from such differentiated cells: the search for alternatives to organ/islet transplantation strategies via stem cells differentiation is an ongoing task, significant goals having been achieved in most experimental settings (e.g. insulin production and euglycaemia restoration), though caution is still needed to ensure safe and durable effects in vivo. MSC are obtainable in …